Abstract

The existence of subpopulations of cells in cancers with increased tumor-initiating capacities and self-renewal potential, often termed "cancer stem cells," is a much discussed and key area of cancer biology. Such cellular heterogeneity is very important because of its impact on therapy and especially states of treatment resistance. A major question is whether there is plasticity for evolution of these cell states during tumorigenesis that can involve movement between cell populations in a reversible fashion. In this review, we discuss the possible role of epigenetic abnormalities as well as genetic alterations in such dynamics and in the creation of cellular heterogeneity in cancers of all types.

During oncogenesis, environmental stress such as chronic inflammation, accumulating reactive oxygen species (ROS) or aging, may promote clonal expansion of cells with genetic or epigenetic abnormalities. These cells then acquire further mutations or epigenetic alterations and become founder tumor cells that initiate pre-cancer or cancer. The evolution of tumor clones continues as tumors develop. In an established tumor, the parental subclone may acquire new driver or passenger mutations (genetic subclone), or undergo epigenetic alterations on the levels of chromatin or DNA methylation, or both (epigenetic subclones). Some subclones may acquire mutations in epigenetic modifying proteins resulting in emergence of epigenetic changes (genetic/epigenetic subclones). Either genetic or epigenetic subclones can exhibit different functional attributes from the parental clone in terms of self-renewing capacity, drug tolerance or metastatic potential. Thus, both genetic and epigenetic mechanisms contribute to the intra-tumoral heterogeneity.

In normal embryonic and adult stem cell states, many developmental genes maintain both active (H3K4me3) and repressed(H3K27me3) marks, or bivalent chromatin, at their promoter regions. This state helps maintain genes gene in poised states for transcription. During normal differentiation, bivalent domains will resolve into either active marks (H3K4me3) attendant to active transcription of certain differentiation-related genes, or repressive marks (H3K27me3) marks which accompany silencing of stem cell-related genes. Under certain circumstances, the resolution of bivalent domains can be reversed and cells may undergo dedifferentiation. Also, bivalency of genes may arise in cell populations distal to stem cell states. In a cancer cell, these chromatin shifts may be vital to cellular plasticity. Some of the bivalent genes may assume cancer-specific promoter DNA hypermethylation and, thus, be locked in a more permanent silenced state.

Cancer may derive from different compartments during normal cell differentiation and have plasticity for movement of cell subtypes

During normal cell differentiation, self-renewing tissue stem cells undergo a series of chromatin state transitions and give rise to progenitor and differentiated cells. Cellular transformation may take place at different stages during normal differentiation, and give rise to malignant cells that carry similar, but abnormal chromatin states relative to their normal counterparts. Notably, tumor cells may exhibit a cellular plasticity through which they can switch between more stem cell-like states and more differentiated cell states through mesenchymal-epithelial transition (MET) or epithelial-mesenchymal transition (EMT).

Genetic and epigenetic mechanisms for drug resistance and implications of epigenetic therapy

Top panel - cancers may consist of different subclones that carry a founder mutation(s) alone, or additional acquired mutations, that confer drug resistant states. When treated with targeted therapies, a pre-existing drug tolerant clone may remain unaffected and through outgrowth can come to dominate the entire cancer population. Middle panel - cancer subclones with epigenetic-mediated drug tolerance may exist in the original caner population or develop as a result of targeted chemotherapy. The drug tolerance may be reversed and cells may return to the sensitive epigenetic state after a prolonged drug withdrawal or after the tumor is treated with epigenetic therapy, such as low dose histone deacetylase (HDAC) inhibitors and/or DNA demethylating agents. Lower panel - epigenetic therapy may convert cancer cells in a drug-resistance state to a drug-sensitive state, thereby sensitizing the cells to targeted chemotherapy that was not effective for the original cancer population.